Molecular imaging methods to visualize the neuropathology of Alzheimer?s disease (AD) in vivo provide an unprecedented opportunity to understand early stage AD by testing hypotheses informed by human neuropathology and animal models. A fuller understanding of the neurobiology of early AD and its clinical progression is essential to identify individuals at risk and to identify targets for prevention and treatment. To maximize the benefit from disease-modifying therapies, individuals must be identified and treated in the early stages, including mild cognitive impairment (MCI). Only by doing so, is it possible to prevent progressive spreading of neuropathology and emergence of cognitive deficits and neuropsychiatric symptoms (NPS). Multi-radiotracer PET studies of A? and 5-HT by the PI and colleagues in amnestic, multi-domain, MCI (aMCI- MD) and cognitively normal elderly demonstrated progressive, cortical and limbic 5-HT degeneration over the course of MCI, linked to network dysfunction, that was greater and more widespread than cortical A?, cerebral atrophy or cerebral blood flow deficits. Cortical and limbic 5-HT degeneration was a more powerful predictor of cross-sectional and longitudinal memory impairment than A?. Human data and animal models show the synergistic effect of Tau on both A? and 5-HT degeneration. Tau overlaps more than A? with loss of 5-HT in cortical and 5-HT-rich limbic regions, is more temporally linked to cognitive deficits and decline and is better correlated with cognitive impairment. Thus, in vivo imaging of 5-HT combined with Tau and A?, may represent a powerful predictor of cognitive decline and emergence of NPS. Lower 5-HT transporters (SERT) overlapped to a greater extent with Tau in limbic regions than A?. A longitudinal molecular imaging study is proposed in normal aging and amnestic, multi-domain, MCI (aMCI-MD) with high resolution PET scans for 5-HT transporter availability (SERT), Tau and A?. To evaluate SERT, and its relationship to Tau and A?, in aMCI-MD and normal controls at baseline and longitudinal follow-up. 2. To evaluate SERT, Tau and A? in relation to cognitive deficits and NPS, in aMCI-MD and normal controls at baseline and longitudinal follow-up. The hypotheses will be tested that relative to healthy controls, patients with aMCI-MD will have lower baseline and longitudinal decreases in SERT, higher baseline and greater increases in Tau and less baseline difference and less change over time in A? .Lower SERT and decreases over time, in combination with greater increases in Tau, in contrast to increases in A?, will be associated with greater cognitive deficits (episodic, verbal memory) and NPS (affective cluster) and worsening of cognition and NPS to a greater extent in aMCI-MD compared to controls. Elucidating the role of 5-HT in relation to Tau and A? in cognitive decline in aMCI-MD will have fundamental implications for the design of prevention and intervention studies targeting 5-HT, studies of other neurotransmitters vulnerable to neurodegeneration (norepinephrine) and hypothesized mechanisms underlying their vulnerability (e.g. oxidative stress, neuroinflammation).